The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects

Gripp, Karen W.; Baker, Laura; Robbins, Katherine; Stabley, Deborah L.; Bellus, Gary A.; Kolbe, Verena; Nauth, Theresa; Rosenberger, Georg

doi:10.1038/s41431-020-0662-4

Cited by 7 publications

(15 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…were induced to bind HRAS to RAF1-RBD. This effect was also observed in previous studies (Gripp et al, 2020;Lorenz et al, 2013). In our study, cells transfected with intragenic HRAS duplications or p.Gly12Val did not show increased phosphorylation of ERK despite enhanced ELK transactivation.…”

Section: Discussionsupporting

confidence: 91%

“…The constitutive retention of exon IDX, resulting in a hyperactive HRAS protein, has been identified in a patient with CS (Pantaleoni et al, 2017). Germline intragenic duplications in HRAS have been identified in three patients with CS, including p.(Glu63_Asp69dup) in two patients and p.(Glu62_Arg68dup) in one patient (Gripp et al, 2020; Lorenz et al, 2013; Xu et al, 2015). In contrast, intragenic duplications in KRAS or NRAS have not been identified in patients with RASopathies.…”

Section: Discussionmentioning

confidence: 99%

“…Activating mutations in the amino acid residues 12, 13, or 61 resulted in elevated levels of GTP‐bound RAS due to the impaired basal GAP‐stimulated hydrolysis of GTP. Recently, intragenic duplications of RAS have been identified in patients with CS or cancers (Gremer et al, 2010; Gripp et al, 2020; Lorenz et al, 2013; Xu et al, 2015). The reported intragenic duplications are located in the switch I region (p.(Glu37dup)) and the switch II region (p.(Glu63_Asp69dup) or p.(Glu62_Arg68dup)).…”

Section: Introductionmentioning

confidence: 99%

“…The reported intragenic duplications are located in the switch I region (p.(Glu37dup)) and the switch II region (p.(Glu63_Asp69dup) or p.(Glu62_Arg68dup)). Functional analysis of intragenic duplications showed impaired GAP activation, reduced intrinsic and GAP-stimulated GTP hydrolysis (Eijkelenboom et al, 2019), or decreased interaction with the effector proteins PI3K and NF1-GAP (Gripp et al, 2020). These variants result in increased steady-state phosphorylation of MEK1/2 and ERK 1/2, RAS downstream effectors (Gripp et al, 2020).…”

mentioning

confidence: 99%

“…Functional analysis of intragenic duplications showed impaired GAP activation, reduced intrinsic and GAP-stimulated GTP hydrolysis (Eijkelenboom et al, 2019), or decreased interaction with the effector proteins PI3K and NF1-GAP (Gripp et al, 2020). These variants result in increased steady-state phosphorylation of MEK1/2 and ERK 1/2, RAS downstream effectors (Gripp et al, 2020). However, the impact of intragenic HRAS duplications on morphogenesis during the development of model organisms has not yet been reported.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

et al. 2021

View full text Add to dashboard Cite

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

et al. 2021

View full text Add to dashboard Cite

show abstract

A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

Hou

Evenson

Corliss

et al. 2023

Genetics in Medicine

View full text Add to dashboard Cite

A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome

et al. 2022

Self Cite

View full text Add to dashboard Cite

Costello syndrome (CS) is caused by heterozygous HRAS germline mutations. Most patients share the HRAS variant p.Gly12Ser that is associated with a typical, homogeneous phenotype. Rarer pathogenic HRAS variants (e.g., p.Thr56Ile) were identified in individuals with attenuated CS phenotypes. The obvious phenotypical variability reflects different dysfunctional consequences of distinct HRAS variants. We report on two boys with the novel de novo HRAS variant c.466 C > T p.(Phe156Leu). Both had severe feeding difficulties, airway obstruction and developmental delay, which are typical findings in CS. They showed subtle facial and dermatologic features consistent with attenuated CS. They significantly differed in their musculoskeletal, cardiovascular and endocrinologic manifestations underscoring the clinical variability of individuals with identical, in particular rarer pathogenic HRAS variants. Functional studies revealed enhanced effector-binding, increased downstream signaling activation and impaired growth factor-induced signaling dynamics in cells expressing HRASPhe156Leu. Our data further illustrate the molecular and phenotypic variability of CS.

show abstract

The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects

Cited by 7 publications

References 17 publications

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome

Contact Info

Product

Resources

About